4-Oxa prostaglandin A-type compounds

ABSTRACT

This invention is a group of 3- and 4- oxa PG-type compounds, and processes for making them. These compounds are useful for a variety of pharmacological purposes, including antiulcer, inhibition of platelet aggregation, increase of nasal patency, labor inducement at term, and wound healing.

United States Patent H91 Nelson 5] Dec. 2, 1975 4-OXA PROSTAGLANDINA-TYPE' 260/488 R: 260/50l.l: 260/5(ll.l5: COMPOUNDS. zoo/501.17;zoo/501.2; 260/514 D 75 I [51] Int. Cl. C07C 61/38: C07C 69/74 I l 1;?i' ss Field of Search 260/468 D. 514 0. 514 CA [73] Assignee: {TheUpjohn Conipa ny, Kalamazoo. [56] References Cited A ":v FOREIGN PATENTSOR APPLlCATlONS [22] Filed: I 1 Apr. l7, l074. 2.036.47! 2/l97l Germany260/468 2| Appl. No.: 461,496

' Primary Examiner-Robert Gerstl PP flb Attorney. Agent. or Firm-MorrisL. Nielsen [63] Continuation of Ser. No. 332.279. Feb. l3. i973.

abandoned. which is a continuation-impart of Set. 57 TR T No.47.l69,]uno I7. 1970. abandoned.

This invention is a group of 3- und 4- oxa PG-lypc rorelin D..Compounds. and PrOCCSSCS (Dr maklng them. Th'CSC I compounds are usefulfor a variety of pharmacological y Kinda "9 purposes. includingantiulcer. inhibition of platelet ag- V d s. 260,468 26012" 260,268gregat on increase of nasal patency labor in ucemem 260/247.2 R;260/293265; 260/326.2; 260/4l0;'260/424.4; 2601434 R; 260/448 R;

at term. and wound healing.

38 Claims. No Drawings 4-OXA PROSTAGLANDIN A-TYPE COMPOUNDS CROSSREFERENCE TO RELATED APPLICATIONS This application is a continuation ofmy copending application Ser. No. 332,279. filed Feb. 13. 1973. nowabandoned, which was a continuation-in-part of my then copendingapplication Ser. No. 47,169. filed June l7, i970, now abandoned.

BACKGROUND OF THE INVENTION This invention relates to compositions ofmatter, and to methods and intermediates for producing them. in

particular, the several aspects of this invention relate to novelanalogs of some of the known prostaglandins, for example, prostaglandinE, (PGE prostaglandin E, (PGEQ, prostaglandin F (PGF, a and PEG, 3prostaglandin F, (PGF, and PGF, prostaglandin A, (POM), prostaglandin A,(PGKQ, prostaglandin B, (PGB prostaglandin B, (P083). the correspondingPG 's. and the dihydro PG, derivatives, to novel methods for producingthose novel prostaglandin analogs, and to novel chemical intermediatesuseful in those novel methods.

Each of the above-mentioned known prostaglandins is a derivative ofprostanoic acid which has the following structure and atom numbering:

coon Wt I a l O A systematic name for prostanoic acid is 7-[(2B-octyl)-cyclopentl a-yl ]heptanoic acid.

PGE, has the following structure:

, COOH PGA, has the following structure:

that s own for the corresponding PG compound except that in each, C-5and G6 are linked with a cis carhon-carbon double bond. For example.PGE, has the following structure:

Vll

Each of the known PG prostaglandins has a structure the same as that ofthe PG; compounds except that in each, C-l7 and C-l8 are linked with acis carboncarbon double bond. For example, POE; has the followingstructure:

Vlll

Each dihydro derivative of POE PGF a PGF, 3 PGA and PGB, has a structurethe same as that shown for the corresponding PG, compound except that ineach, C-l 3 and C14 are linked with a carbon-carbon single bond. Forexample, dihydro-PGE, has the following structure:

The prostaglandin formulas mentioned above'cach have several centers ofasymmetry. As drawn, formulas II to IX each represents the particularoptically active form of the prostaglandin obtained from certainmammalian tissues, for example, sheet vesicular glands, swine lung, andhuman seminal plasma, or by reduction or dehydration of a prostaglandinso obtained. See, for

example. Bergstrom et al.. Pharmacol. Rev. 20. l (1968). and referencescited therein. The mirror image of each formula represents a molecule ofthe enantiomer of that prostaglandin. The racemic form of theprostaglandin consists of equal numbers of two types of molecules. onerepresented by one'of the above formuins and the other represented bythe mirror image of that formula. Thus. both formulas are needed todefine a raeemic prostaglandin. See Nature 212. 38 (1966) for discussionof the stereochemistry of the prostaglandins.

in formulas l-lX. as well as in the formulas given hereinafter. brokenline attachments to the cyclopentane ring indicate substituents in alphaconfiguration. i.e.. below the plane of the cyelopentane ring. Heavysolid line attachments to the cyclopentane ring indicate substituents inbeta configuration. i.e.. above the plane of the cyclopentane ring.

Prostaglandins with carboxyl-terminated side chains attached to thecyclopentane ring in beta configuration are also known. These arederivatives of 8-iso-prostanoic acid which has the following formula:

A systematic name for 8-iso-prostanoic acid is 7-[(2B- octyl)-cyclopent-lp-yl]heptanoic acid.

The side-chain hydroxy at 015 in formulas ii to IX is in alpha (S)configuration. See Nature 212. 38 (1966) for discussion of thestereochemistry of the prostaglandins.

PGE.. PGE,. dihydro-PGE and the corresponding PGF a PGF 8 PGA. and P08compounds. and their esters. acylates. and pharmacologicaily acceptablesalts. are extremely potent in causing various biological responses. Forthat reason. these compounds are useful for pharmacological purposes.See. for example. Bergstrom et al.. Pharmacol. Rev. 20. l (1968). andrefercnces cited therein. A few of those biological responses aresystemic blood pressure lowering in the case of the PCB and PGAcompounds as measured, for example. in anesthetized (pentobarbitalsodium) 'pentoliniumtreated rats with indwelling aortic and right heartcannulas; stimulation of smooth muscle as shown, for example. by testson strips of guinea pig ileum. rabbit duodenum. or gerbil colon;potentiation of other smooth muscle stimulants; antilipolytic activityas shown by antagonism of epinephrine-induced mobilization of free fattyacids or inhibition of the spontaneous release of glycerol from isolatedrat fat pads; inhibition of gastric secretion in the case of the PGE andPGA compounds as shown in dogs with secretion stimulated by food orhistamine infusion; activity on the central nervous system; controllingspasm and facilitating breathing in asthmatic conditions; decreasingblood platelet adhesivcness as shown by platelet-to-glass adhesiveness.and inhibition of blood platelet aggregation and thrombus formationinduced by various physical stimuli. e.g.. arterial injury. and variousbiochemical stimuli. e.g.. ADP. ATP. serotonin. thrombin. and collagen;and in the case of the P and P08 compounds. stimulation of epidermalproliferation and keratinization as shown when applied in culture toembryonic chick and rat skin segments.

Because of these biological responses. these known prostaglandins areuseful to study. prevent. control. or alleviate a wide variety ofdiseases and undesirable physiological conditions in birds and mammals.including humans. useful domestic animals. pets. and zoologicalspecimens. and in laboratory animals. for example. mice. rats. rabbits.and monkeys.

For example. these compounds. and especially the POE compounds. areuseful in mammals. including man. as nasal decongestants. For thispurpose. the compounds are used in a dose range of about 10 pg. to about[0 mg. per ml. of a phannacologically suitable liquid vehicle or as anaerosol spray. both for topical application.

The PGE. PGF PGF 3 and PGA compounds are useful in the treatment ofasthma. For example. these compounds are useful as bronchodilators or asinhibitors of mediators. such as SRS-A. and histamine which are releasedfrom cells activated by an antigen-antibody complex. Thus. thesecompounds control spasm and facilitate breathing in conditions such asbronchial asthma. bronchitis. bronchiectasis. pneumonia and emphysema.For these purposes. these compounds are administered in a variety ofdosage forms. e.g.. orally in the form of tablets. capsules. or liquids;rectally in the form of suppositories; parenterally. subcutaneously. orintramuscularly. with intravenous administration being preferred inemergency situations; by inhalation in the form of aerosols or solutionsfor nebuiizers'. or by insufflation in the form of powder. Doses in therange of about 0.0l to 5 mg. per kg. of body weight are used 1 to 4times a day. the exact dose depending on the age. weight, and conditionof the patient and on the frequency and route of administration. For theabove use these prostaglandins can be combined advantageously with otheranti-asthmatic agents. such as sympathomimetics (isoproterenol.phenylephrine. ephedrine. etc.); xanthine derivatives (theophylline andaminophylline); and cortico-steroids (ACT H and predinisolone).regarding use of these compounds see South African Pat. No. 681.055.

The POE and PGA compounds are useful in mammals. including man andcertain useful animals. e.g.. dogs and pigs. to reduce and controlexcessive gastric secretion. thereby reducing or avoidinggastrointestinal ulcer formation. and accelerating the healing of suchulcers already present in the gastrointestinal tract. For this purpose.the compounds are injected or infused intravenously. subcutaneously. orintramuscularly in an infusion dose range about 0.1 Lg. to about 500 pg.per kg. of body weight per minute or in a total daily dose by injectionor infusion in the range about (H to about 20 mg. per kg. of body weightper day. the exact dose depending on the age. weight. and condition ofthe patient or animal. and on the frequency and route of administration.

The PGE. PGF and PGF 5 compounds are useful whenever it is desired toinhibit platelet aggregation. to reduce the adhesive character ofplatelets. and to remove or prevent the formation of thrombi in mammals.including man. rabbits. and rats. For example. these compounds areuseful in the treatment and prevention of myocardial infarcts. to treatand prevent post-ope rative thrombosis. to promote patency of vasculargrafts following surgery. and to treat conditions such asatherosclerosis. arteriosclerosis. blood clotting defects due tolipemia. and other clinical conditions in which the underlying etiologyis associated with lipid imbalance or hyperlipidemia. For thesepurposes. these compounds are administered systemically. e.g..intravenously. subcutaneously. intramuscularly. and in the form ofsterile implants for prolonged action. For rapid response. especially inemergency situations. the intravenous route of administration ispreferred. Doses in the range about 0.005 to about 20 mg. per kg. ofbody weight per day are used. the exact dose depending on the age.weight. and condition of the patient or animal. and on the frequency androute of administration.

The PGE. PGF and PGF compounds are especially useful as additives tolood. blood products. blood substitutes. and other fluids which are usedin artificial extracorporeal circulation and perfusion of isolated bodyportions. e.g.. limbs and organs. whether attached to the original body.detached and being preserved or prepared for transplant. or attached toa new body. During these circulations and perfusions. aggregatedplatelets tend to block the blood vessels and portions of thecirculation apparatus. This blocking is avoided by the presence of thesecompounds. For this purpose. the compound is added gradually or insingle or multiple portions to the circulating blood. to the blood ofthe donor animal. to the perfused body portion. attached or detached. tothe recipient. or to two or all of those at a total steady state dose ofabout 0.00l to mg. per liter of circulating fluid. It is especiallyuseful to use these compounds in laboratory animals. e.g.. cats, dogs.rabbits, monkeys. and rats, for these purposes in order to develop newmethods and tech niques for organ and limb transplants.

PGE compounds are extremely potent in causing stimulation of smoothmuscle, and are also highly active in potentiating other known smoothmuscle stimulators. for example. oxytocic agents. e.g.. oxytocin, andthe various ergot alkaloids including derivatives and analogs thereof.Therefore, PGE,. for example. is useful in place of or in combinationwith less than usual amounts of these known smooth muscle stimulators.for example. to relieve the symptoms of paralytic ileus. or to controlor prevent atonic uterine bleeding after abortion or delivery. to aid inexpulsion of the placenta. and during the puerperium. For the latterpurpose, the PGE compound is administered by intravenous infusionimmediately after abortion or delivery at a dose in the range about 0.01to about SO'ug. per kg. of body weight per minute until the desiredeffect is obtained. Subsequent doses are given by intravenous.subcutaneous. or intramuscular injection or infusion during puerperiumin the range 0.01 to 2 mg. per kg. of body weight per day. the exactdose depending on the age. weight. and condition of the patient oranimal.

The PGE and PGA compounds are useful as hypotensive agents to reduceblood pressure in mammals. including man. For this purpose. thecompounds are administered by intravenous infusion at the rate about0.01 to about 50 pg. per kg. of body weight per minute or in single ormultiple doses of about 25 to 500 pg. per kg. of body weight total perday.

The PGE. PGF and PGF compounds are useful in place of oxytocin to inducelabor in pregnant female animals. including man. cows. sheep. and pigs.at or near term. or in pregnant animals with intrauterine death of thefetus from about weeks to term. For this purpose. the compound isinfused intravenously at a dose of 0.0l to 50 pg. per kg. of body weightper minute until or near the termination of the second stage of labor.i.e.. expulsion of the fetus. These compounds are 6 especially usefulwhen the female is one or more weeks post-natural and natural labor hasnot started. or 12 to 60 hours after the membranes have ruptured andnatural labor has not yet started. An alternative route oftidministration is oral.

The PGE. PGF and PCP compounds are useful for controlling thereproductive cycle in ovuluting female mammals. including humans andanimals such as monkeys, rats. rabbits. dogs. cattle. and the like. Bythe term ovulating female mammals is meant animals which are matureenough to ovulate but not so old thtll regular ovulation has ceased. Forthat purpose POP, for example. is administered systemically at a doselevel in the range 0.01 mg. to about 20 mg. per kg. of body weight ofthe female mammal. advantageously during a span of time startingapproximately at the time of ovulation and ending approximately at thetime of menses or just prior to menses. lntravaginal and intrauterineare alternative routes of administration. Additionally. expulsion of anembryo or a fetus is accomplished by similar administration of thecompound during the first third of the nomtal mammalian gestationperiod.

'The POE and PGF compounds are useful in causing cervical dilation inpregnant and nonpregnant female mammals for purposes of gynecology andobstetrics. in labor induction and in clinical abortion produced bythese compounds. cervical dilation is also observed. in cases ofinfertility. cervical dilation produced by PCB and PGF compounds isuseful in assisting sperm movement to the uterus. Cervical dilation byprostaglandins is also useful in operative gynecology such as D and C(Cervical Dilation and Uterine Curettage) where mechanical dilation maycause perforation of the uterus.

cervical tears. or infections. It is also useful in diagnosticprocedures where dilation is necessary for tissue examination. For thesepurposes. the PGF. and PCP compounds are administered locally orsystemically. PGE for example. is administered orally or vaginally atdoses of about 5 to 50 mg. per treatment of an adult female human. withfrom one to five treatments per 24 hour period. POE, is alsoadministered intramuscularly or subcutaneously at doses of about one to25 mg. per treatment. The exact dosages for these purposes depend on theage. weight. and condition of the patient or animal.

As mentioned above. the PGE compounds are potent antagonists ofepinephrine-induced mobilization of free fatty acids. For this reason,this compound is useful in experimental medicine for both in vitro andin vivo studies in mammals. including man. rabbits, and rats. intendedto lead to the understanding. prevention. symptom alleviation, and cureof diseases involving abnormal lipid mobilization and high free fattyacid levels. e.g., diabetes mellitus. vascular diseases, andhyperthyroidism.

The PGA compounds and derivatives and salts thereof increase the flow ofblood in the mammalian kidney, thereby increasing volume and electrolytecontent of the urine. For that reason, PGA compounds are useful inmanaging cases of renal disfunction. especially those involving blockageof the renal vascular bed. lllustratively. the PGA compounds are usefulto alleviate and correct cases of edema resulting. for example. frommassive surface burns. and in the management of shock. For thesepurposes. the PGA compounds are preferably first administered byintravenous injection at a dose in the range of i0 to 1000 pg. per

7 kg. of body weight or by intravenous infusion at a dose in the range0.1 to 20 pg. per kg. of body weight per minute until the desired effectis obtained. Subsequent doses are given by intravenous. intramuscular.or subcutaneous injection or infusion in the range 0.05 to 2 mg. per kg.of body weight per day;

The PGE and P08 compounds promote and accelerate the growth of epidermalcells and keratin in animnls. including humans. useful domestic animals.pets. zoological specimens. and laboratory animals. For that reason.these compounds are useful to promote and acccleralc healing of skinwhich has been damaged. for example. by burns. wounds. and abrasions.and after surgery. These compounds are also useful to promote andaccelerate adherence and growth of skin autografts. especially small.deep (Davis) grafts which are intended to cover skinless areas bysubsequent outward growth rather than initially. and to retard rejectionof homografts.

For these purposes. these compounds are preferably administeredtopically at or near the cite where cell growth and keratin formation isdesired. advantagcously as an aerosol liquid or micronized powder spray.as an isotonic aqueous solution in'the case of wet dressings. or as alotion. cream. or ointment in combination with the usualpharmaceutically acceptable diluents. in some instances. for example.when there is substantial fluid loss as in the case of extensive burnsor skin loss due to other causes. systemic administration isadvantageous. for example. by intravenous injection or infusion.separate or in combination with the usual infusions of blood. plasma. orsubstitutes thereof. Alternative routes of administration aresubcutaneous or intramuscular near the site, oral. sublingual, buccal.rectal. or vaginal. The exact dose depends on such factors as the routeof administration. and the age. weight, and condition of the subject. Toillustrate. a wet dressing for topical application to second and/orthird degree burns of skin area to 25 square centimeters wouldadvantageously involve use of an isotonic aqueous solution containing lto 500 ugJml. of the P68 compound or several times that concentration ofthe PGE compound. Especially for topical use. these prostaglandins areuseful in combination with antibiotics, for example. gentamycin.neomycin. polymyxic B. bacitracin. spectinomycin. and oxytetracycline.with other antibacterials. for example. mafenide hydrochloride.sulfadiazine. furazolium chloride. and nitrofurazone. and with corticoidsteroids. for example. hydrocortisone, prednisolone. methylprednisolone.and fluprednisolone. each of those being used in the combination at theusual conccntration suitable for its use alone.

SUMMARY OF THE INVENTION it is a purpose of this invention to providenovel 3-oxa and 4-oxa prostaglandin analogs, and processes for makingthem.

The novel prostaglandin analogs of this invention each have an oxygen(-0-) in place of the methylene (-CH,-) moiety at the 3-position or atthe 4-position ot the prostanoic acid formula (I). For example. 3 oxaPGF... one of the novel compounds of this invention. is represented bythe formula:

d DH The novel compound. 4-oxa-PGE, is represented by the formula:

Xll

0 I OH Xi l l XIV \:=/ 0 ACOOH XV H OH CH C C-CH; 0-CH C00H XVI XVl lBased on its relationship to PGE, and prostanoic acid, the compound offormula XIII is named 3-oxa-4-nor- PGEi; the compound of formula XlV isnamed 4-oxa-4n.4b-dihomol 3 I 4-dihydrol S-beta-PG F l u: the compoundof formula XV is named 3-oxa-l9.20 dinor-POM; the compound of formulaXVl is named 3-oxa-5.6dehydro-20-methyl-PG8:: and the compound offormula XVII is named 3-oxa-$.6-Eehydro- 20-methyl-PGB and the compoundof formula XV ii is named 3-oxa-4a-homo-PG FHB.

These names for the compounds oi formulas Xlll to XVil are typical ofthe names used hereinafter for the novel compounds of this invention.These names can better be understood by reference to the structure andnumbering system of prostanoic acid (Formula I, above). That formula hasseven carbon atoms in the carboxy-terminated chain and eight carbonatoms in the hydroxy-containing chain. in these names, ii-oxa and t-oxaindicate an oxa oxygen in place of the S-methylene and 4-methylene,respectively of the PG compound.

The use of nor" or "dinor" in the names for the novel compounds of thisinvention indicates the absence of one or two of the chain carbon atomsand the attached hydrogen atoms. The number or numbers in front of nor,or dinor indicate which of the original prostanoic acid carbon atoms aremissing in the named compound.

The use of homo" or dihomo as in the names of the formula-XIV and -XVllexamples indicate one or two additional carbon atoms in thecarboxy-terminated side chain. In the name of the formula-XIV example4a,4b-dihomo" indicates two additional carbon atoms specifically betweenthe oxygen atom at 4 and the C-5 carbon atom. There are, therefore,eight carbon atoms and one oxygen atom in that side chain instead of thesix carbon atoms and one oxygen atom of the normal 3-oxa structure ofthis invention.

in the name of the formula-XVI example, methyl" indicates that a methylgroup replaces a hydrogen on C-20. The methyl-terminated chain of thatexample therefore has nine carbon atoms.

Where there is branching or fiuoro substitution in the side chains, thepoints of attachment to the side chains are indicated in theconventional manner, following the atomic numbering of the prostanoicacid skeleton (l).

Novel compounds of this invention with epi configuration for the hydroxyat C-lS are so designated by using "IS-beta" in the name. An example isthe name given above for the compound of formula XIV. if 15- beta doesnot appear in the name, the natural configuration for the G15 hydroxy,identified as the "S" configuration for PS5,, is to be assumed.

The following formulas represent the novel 3-oxa and 4-oxa compounds ofthis invention in the same optically active form as the naturallyoccuring prostaglandins.

H l l H01 C-R it O TS 7 -o-c-c-cooa XXI l unw n 0R,

-cooR R l i a l @CliyC' C-Cq H -O-f-f-COOR, c-c

H 0 C C Lil Lill

LIV

LVI

Fonnulas XVlll to XXVlI represent 3-oxa and 4-oxa compounds of the POEtype. Formulas XXVlll to XXXVI] represent 3-oxa and 4-oxa compounds ofthe PGF type. Formulas XXXVII] to XLVll represent 3-oxa and 4-oxacompounds of the PGA type. Formulas XLVIll to LVll represent 3-oxa and4-oxa compounds of the PCB type.

In formulas XVlll to LVll, r is hydrogen, alkyl of one to 12 carbonatoms, inclusive, cycloalkyl of 3 to l0 carbon atoms, inclusive, aralkylof 7 to 12 carbon atoms, inclusive, phenyl, phenyl substituted with oneto 3 chloro or alkyl of one to .4 carbon atoms, inclusive, or ethylsubstituted in the B-position with 3 chloro, 2 or 3 bromo, or I, 2, or 3iodo. R, is alkyl of one to l0 carbon atoms, inclusive, substituted withzero to 3 fluoro. Q is Q is R, OH or R, H

wherein R, is hydrogen or alkyl of one to 4 carbon atoms, inclusive. R,is alkyl of one to 4 carbon atoms, inclusive, substituted with zero,one, 2 or 3 fluoro. R R R and R, are hydrogen or alkyl of one to 4carbon atoms, inclusive. The divalent moiety --C,,H represents alkyleneof one to 10 carbon atoms, inclusive, with one to 5 carbon atoms,inclusive, between CH,- and O. The divalent moiety C,,,H representsalkylene of one to 9 carbon atoms, inclusive, with one to 4 carbonatoms, inclusive, between CH and O. The divalent moiety C H representsalkylene of one to 8 carbon atoms, inclusive, with one, 2, or 3 carbonatoms between --CH=CH- or C I C- and O. The divalent moiety --C H- 2Qrepresents alkylene of one to 7 carbon atoms, inclusive, with one or 2carbon atoms between CH= CH or "C C and ..O The divalent moiety -.CH==CHor ..C C O The divalent I moiety .C;H represents alkylene of one to 4carbon atoms, inclusive. The wavy lineindicates attachment of thehydroxyl group to the ring in alpha or beta configuration.

Formulas XVIII through LVll include the separate isomes wherein Q iseither R; CH or R; OH,

i.e. where the hydroxyl is in either alpha (natural) or betaconfiguration. Referring to the prostanoic acid atom numbering (formula1 above), the point of attachment corresponds to C-l5, and, herein,regardless of the variation in the C-1 to C-7 carboxy chain, theseepimers are referred to as C-l5 epimers.

Formulas XXVlll through XXXVll wherein the C-9 hydroxyl (followingprostanoic acid atom numbering) is attached to the cyclopentane with awavy line include both PGF and PGF type compounds.

included in formulas XX, XXI, xXX, XXX], XL, XL], L, and Ll are both thecis and the trans compounds with respect to the O5 to C-6 double bond inthe carboxyl-tenninated side chain. In all of the compounds containingthe C -to-C double bond, that double bond is in trans configuration, andthe chain containing that moiety is attached to the cyclopentane ring inbeta configuration in compounds encompassed by formulas XVlll to XLVll.

The novel 3-oxa and 4-oxa compounds of this invention include racemiccompounds and both optically active enantiomeric forms thereof. Asdiscussed hereinample in Chart E, to define not only the opticallyactive form but also the racemic compounds which generally undergothe'same reactions.

Fonnula XVIII represents 3oxa-PGE, hereinabove) when C,,I-I,,, is(CH,)=-,

out! on,

R R and R. are hydrogen, and R, is n-pentyl.

With regard to formulas XVIII to LVII, examples of alkyl of one to 4carbon atoms, inclusive. are methyl, ethyl, propyl, butyl, and isomericforms thereof. Examples'of alkyl of one to '8 carbon atoms, inclusive,are those given above, and pentyl', hexyl, heptyl, octyl, and isomericforms thereof. Examples of alkyl of one to 12 carbon atoms, inclusive,are those given above, and nonyl, decyl, undecyl, dodecyl, and isomericforms thereof. Examples of cycloalkyl of 3 to l carbon atoms,'inclusive,which includes alkyl-substituted cycloalkyl, are cyclopropyl,Z-methylcyclopropyl, 2,2-f dimethylcyclopropyl, 2,3-diethylcyclopropyl,2-butylcyclopropyl, cyclobutyl, 2 methylcyclobutyl, 3-propylcyclobutyl,2,3,4-triethylcyclobutyl, cyclopentyl, 2,2- dimethylcyclopentyl,3-pentylcyclopentyl, 3-tert-butylcyclopentyl, cyclohexyl,4-tert-butylcyclphexyl, 3-isopropyleyclohexyl, 2,2-dimethylcyclohexyl,cycloheptyl,,cyclooctyl, cyclononyl, and cyclodecyl, Examples of aralkylof 7 to 12 carbon atoms, inclusive, are benzyl, phenethyl, l-phenylethyl, 2- phenylpropyl, 4 phenylbutyl, 3-phenylbutyl,Z-(l-naphthylethyl), and l-(2-naphthylmethyl), Examples ofphenyl-substituted by one to 3 chloro' or alkyl'of one to 4 carbonatoms, inclusive, are p-chlorophenyl, m-chlorophenyl, ochlorophenyl,,2,4-dichlorophenyl, 2,4,6-trichlorophenyl, p-tolyl, m-tolyl, otolyl,p-ethylphenyLp-tert-butylphenyl, 2,5-dimethylphenyl,4-chloro-2-methylphenyl, and 2,4-dichloro-3-methylphenyl.

Examples of alkyl ofone to .l0.carbon atoms, inclusive, substituted withone to 3 fluoro, are fluoromethyl, 2-fluoroethyl, 2-fluorobutyl,3-fluorobutyl, 4-fluorobutyl, S-fluoropentyh 4-fluoroe4-methylpentyl, 3-fluoroisoheptyl, 8-fluorooctyl, 3,4-difluorobutyl, 4,4- difluoropentyl,5,5-difluoropentyl, 5,5,5-trifluoropentyl, and I0,l0,l0-tri fluorodecyl.

Examples of alkylene .within ,the various scopes of C,l-l, C,,,I-I,,,,,C,,H,,,,' CJI, and C,I-I,,,, as those are de-' fined above, aremethylene,'ethylene, trimethylene, tetramethylene, pentarhethylene, andthose alkylene with one or more alkyl ,substituents onone or more carbonatoms thereof, 'e.g.,' .CI-I(CH)--, -C(CI-I,),, -Cl-l(CI'l',Cl-l,)-CH,CH(CH,), CI-I(CI-I- s)-- s). lr s):, ,Cl-l(CI-I;)CI-l,-,-CI'I,CI-I,CH(CI-I,CH,CH- s)' H( s) Hs) HI. ,-CH,-CH,-C(CI'I,),CH,-,'and CH,-CH- ,-CH,CH, Cl-l(CI-I,)-.

The novelformula XVIII-'XXVlIPqE-type 3-oxa and 4-oxa compounds, thenovel formulasXXVIII-XXXVII PGF -type and POF '-type 3-oxa and 4 -oxacompounds, the novel formula XXXVlII-XLVII pGA-type (formula XI 3-oxaand 4-oxa compounds, and the novel formula XLVIll-LVII PGB-type3-oxa'and 4-oxa compounds, and their racemic forms, each cause thebiological responses described above for the PGE, PGF PGF 5 PGA, and P08compounds, respectively, and each of these novel compounds isaccordingly useful for the above-described corresponding purposes, andis used for those purposes in the same manner as described above.

The known PGE, PGF PGF PGA, and PCB compounds uniformly cause multiplebiological responses even at low doses. For example, PCB, and PGE, bothcause vasodepression and smooth muscle stimulation at the same time theyexert antilipolytic activity. Moreover, for many applications, theseknown prostaglandins have an inconveniently short duration of biologicalactivity. In striking contrast, the novel formula XVIII-to-LVII analogsand their racemic forms are substantially more specific with regard topotency in causing prostagIandin-like biological responses, and have asubstantially longer duration of biological activity. Therefore, each ofthese novel prostaglandin analogs is useful in place of one of thecorresponding above-mentioned known prostaglandins for at least one ofthe pharmacological purposes indicated above for the latter, and issurprisingly and unexpectedly more useful for that purpose because ithas a different and narrower spectrum of biological activity than theknown prostaglandin, and therefore is more specific in its activity andcauses smaller and fewer undesired side effects than the knownprostaglandin. Moreover, be cause of its prolonged activity, fewer andsmaller doses of the novel prostaglandin analog can frequently be usedto attain the desired result.

To obtain the optimum combination of biological potency specificity andduration of activity, certain compounds within the scope of formulasXVIII to LVll are preferred. For example, it is preferred that thecarboxyterminated chain in each formula contain a chain of six atomsbetween the carboxyl and the cyclopentane ring. One of those six atomswill be the oxa atom and the other five will be carbon atoms.Accordingly and with reference to formulas XVIII to LVII, it ispreferred that -'C,,H,,,- represent a 3-carbon divalent chain, that-C,,,I-l,,,,- represent a 2-carbon divalent chain, and that-'-C,I'I,,,-- represent a divalent carbon atom. 'I'hese'preferences donot exclude additional carbon atoms (alkyl groups) as branching.

A seven-atom carboxyl terminated chain is not included in the compoundsof formulas XXI, XXIII, XXYII, XXXI, XXXIII, XXXVII, XLI, XLIII, XLVll,LI,-LIII, and LVII, i.e., formulas wherein the carboxytenninated sidechain is 4-oxa and contains a carboncarb on'double or'triple bond. Ineach of those compounds, the q of --C,,I-l,, is at least one, and atleast seven atoms, one oxygen (oxa) and six carbons, arepresentbetween'the carboxyl and the cyclopentane ring. In thesecompounds, the preference is for that minimum chain, i.e., q is one.

Another preference for the compounds of formulas XVIII IO LVII is that RR R R and R be hydrogen or methyl. All of those R groups can behydrogen, all can be methyl, or there can be any of the possiblecombinations of hydrogen and methyl. It is especially preferred forprolonged duration of biological activity that both R, and R. be methyl,and/or that R, be methyl.

Certain variations in the nature of R, in formulas XVIII-XXV,XXVIll-XXXV, XXXVlIl-XLV, and

-CHF-(CH,),-CH; wherein g is one to 5. Alter nately, R, is representedby wherein R. is hydrogen or fiuoro and g is one. 2, 3, 4. or 5. Pentyland .l-fluoropentyl are, of course, included in this preference.

in compounds of formulas XXVI, XXVll, XXXVI, XXXVlI, XLVl, XLVil, Li",and LVll, it is preferred that C,H,, be methylene and that R. be ethyl.t Another advantage of the novel compounds of this invention, especiallythe preferred compounds defined hereinabove, compared with the knownprostaglandins, is that these novel compounds are administeredeffectively orally. sublingually, intravaginally, buccally, or rectally,in addition to usual intravenous, intramuscular, or subcutaneousinjection or infusion methods indicated above for the uses of the knownprostaglandins. These qualities are advantageous because they facilitatemaintaining uniform levels of these compounds in the body with fewer,shorter, or smaller doses,-and make possible self-administration by thepatient.

The POE, PGF, PGF PGA,. and.i-GB type 3-oxa and 4-oxa compounencompassed by formulas XVlll to LV" inciudingthe special classes ofcompounds described above, are used for the purposes described above inthe free acid form, in ester form, or in pharmacologieally acceptablesalt form. When the ester fonn is used the ester is any' of those withinthe above definition of R However, it is preferred that the ester bealkyl of one to 12 carbon atoms, inclusive. Of those aikyi, methyl andethyl are especially preferred for optimum absorption of the compound bythe body or experimental animal system; and straight-chain octyi, nonyl,decyl, undecyl, and dodecyl are especially preferred for prolongedactivity in the body or experimental animal. L T

Pharmacologically acceptable salts of these formula XVlll-to-LVllcompounds useful for the purposes described above are thosewith'pharmacologically acceptable metal cations, ammonium, aminecations, or quaternary ammonium cations. a U .L'

Especially preferred metal cations are those derived from the alkalimetals. e.g., lithium, sodium andpotassium, and from the alkaline earthmetais',"e.'g., magnesium and calcium, although cationic forms of othermetals, e.g., aluminum, "zinc, and iron, are within the scope of thisinvention.

Pharmacologicaliy acceptable amine cations are those derived fromprimary, secondary, or tertiary amines. Examples of suitable amines aremethylamine,

dimethylamine, trimethylar'nine, ethylamine, dibu'tyl amine,triisopropylamine, N-methylhexylamine, decylamine, dodecylamine,allylamine, crotylamine, cyclopentylamine, dicycloheitylarnine.benzylam'me, dibenzylamine, a-phenylethylarnine', B-phenylethylamine,etheylenediamine,'diethylenetriamine, and like 20 aliphatic.cycloaliphatic, and araliphatic amines containing up to and includingabout 18 carbon atoms, as well as heterocyclic amines, e.g., piperidine,morpholine, pyrrolidine, piperazine, and lower-aikyl derivativesthereof, e.g., l-methyipiperidine, 4-ethylmorpholine,l-isopropylpyrrolidine, Z-methylpyrrolidine, 1,4- dimethylpiperazine,Z-methylpiperidine, and the like. as well as amines containingwater-solubilizing or hydrophilic groups, e.g., mono-, di-, andtriethanoiamine,

' ethyldiethanolamine, N-butylethanolamine, Z-aminol-butanol,Z-amino-Z-ethyl-l ,3-propanediol, Z-amino- 2-methyl-l-propanol,tris-(hydroxymethyl)aminomethane, N-phenylethanolamine,N-(p-tert-amylphenyl)- diethanolamine, galactamine, N-methyigiucamine,N- methylglucosamine, ephedrine, phenylephrine, epinephrine. procaine,and the like.

; Examples of suitable pharrnacologically acceptable quaternary ammoniumcations are tetramethylammonium. tetraethylammonium,benzyltrimethylammonium, phenyltriethylammonium, and the like.

The 3-oxa and 4-oxa PGE, PGF PGF PGA, and P08 type compounds encompassedby formulas XVIII to LV" including the special classes of compoundsdescribed above, are also used for the purposes described above in freehydroxy form or in the form wherein the hydroxy moieties are transformedto lower alkanoate moieties, e.g., --OH to OCOCH Examples of loweralkanoate moieties are acetoxy, propionyloxy, butyryloxy, valeryioxy,hexanoyloxy, heptanoyloxy, octanoyloxy, and branched chain alkanoyloxyisomers of those moieties. Especially preferred among these alkanoatesfor the above described purposes are the acetoxy compounds. These freehydroxy and alkanoyloxy compounds are used as free acids, as esters, andin salt form all as described above.

As discussed above, the compounds of formulas XVlll to LV" areadministered in various ways for various purposes; e.g., intravenously,intramuscularly, subcutaneousiy, orally, intravaginally, rectally,bucaily, subiingualiy, topically. and in the form of sterile implantsfor prolonged action. For intravenous injection orinfusion, sterileaqueous isotonic solutions are preferred. For that purpose, it ispreferred because of increased water solubility that R in the formulaXVIII- to-LVll compound be hydrogen or a pharmacoiogically acceptablecation. For subcutaneous or intramuscular injection, sterile solutionsor suspensions of the acid, salt, or ester form in aqueous'ornon-aqueous media are used. Tablets, capsules, and liquid preparationssuch as syrups, elixirs, and simple solutions, with the usualpharmaceutical carriers are used for oral subiinguai administration. forrectal or vaginal administration, suppositories prepared as known in theart are used. For tissue implants, a sterile tablet or silicone rubbercapsule or'other object containing or impregnated with the substance isused.

The 3-oxa and 4-oxa PGE, PGF PGF PGA, and P08 type compounds encompassedby formulas XVlll to LVll are produced by the reactions and proceduresdescribed and exemplified hereinafter.

The various 3-oxa and 4-oxa PGFq -type and PGFB type compoundsencompassed by formulas XXVill-'-XXXVli are prepared by carbonylreduction of the corresponding PGE type compounds encompassed byformulas XVill-XXVll. For example, carbonyl reduction of 3-oxa PGE givesa mixture of 3-oxa 'PGF, and 3-oxa PGF These ring carbonyl reductionsare carried out by methods known in the art for ring carbonyl reductionsof known prostanoic acid derivatives. See, for example. Bergstrom etal., Arkiv Kemi 19, 563 (1963), Acta Chem. Scand. 16, 969 (1962), andBritish Specification No. 1,097,533. Any reducing agent is used whichdoes not react with carbon-carbon double bonds or ester groups.Preferred reagents are lithium(tri-tertbutoxy)aluminum hydride, themetal borohydrides, especially sodium, potassium and zinc borohydrides,and metal trialkoxy borohydrides, e.g., sodium trimethoxyborohydride.The mixtures of alpha and beta hydroxy reduction products are separatedinto the individual alpha and beta isomers by methods known in the artfor the separation of analogous pairs of known isomeric prostanoic acidderivatives. See, for example, Bergstrom et al., cited above, Granstromet al., J. Biol. Chem. 240, 457 (1965), and Green et al., J. LipidResearch 5, 117 (1964). Expecially preferred as separation methods arepartition chromatographic procedures, both normal and reversed phase,preparative thin layer chromatography, countercurrent distributionprocedures, and column chromatography.

The various 3-oxa and 4-oxa PGA-type compounds encompassed by formulasXXXVlll-XLVII are prepared by acidic dehydration of the correspondingPGE type compounds encompassed by formulas XVlll-XX- V11. For example,acidic dehydration of 3-oxa PGE, gives 3-oxa PGA These acidicdehydrations are carried out by methods known in the art for acidicdehydrations of known prostanoic acid derivatives. See, for example,Pike et al., Proc. Nobel Symposium 11, Stockholm (1966), intersciencePublishers, New York, pp. 162-163 (1967); and British Specification1,097,533. Alkanoic acids of 2 to 6 carbon atoms, inclusive, especiallyacetic acid, are preferred acids for this'acidic dehydration. Diluteaqueous solutions of mineral acids, e.g., hydrochloric acid, especiallyin the presence of a solubilizing diluent, e.g., tetrahydrofuran, arealso useful as reagents for this acidic dehydration, although thesereagents may cause partial hydrolysis of an ester reactant.

The various 3-oxa and 4-oxa PGB-type compounds encompassed by formulasXLVll-LVII are prepared by basic dehydration of the corresponding PGEtype compounds encompassed by formulas XVl1lXXVlI, or by contacting thecorresponding PGA compounds encompassed by formulas XXXVlll-XLVll withbase. For example, both 3-oxa P015, and 3-oxa PGA, give 3-0xa PGB, ontreatment with base.

These basic dehydrations and double bond migrations are carried outbymethods known in the art for similar reactions of known prostanoicacidderivatives. See, for example, Bergstrom et al., J. Biol. Chem.238.3555 (1963). The base is any whose aqueous solution has pH greaterthan 10. lfreferred bases are the alkali metal hydroxides. A mixture ofwater and sufficient of a water-miscible alkanol to give a homogeneousreaction mixture is suitable as a reaction medium. The PGE-type orPGA-type compound is maintained in such a reaction medium until nofurther PGB-type compound is formed, as shown by the characteristicultraviolet light absorption near 278 nm for the P08 type compound.

The various transfomiations of 3-oxa and 4-oxa PGE type compounds offormulas XVlll to XXV to the corresponding 3-oxa and 4-oxa PGF PGF PGAand PCB type compounds are shown in Chart A, wherein Q, R,, R and are asdefined above, and wherein A is CH --CH or trans-CH=CH, Q is CHART A t'CHg-V-C00R H6 A'fi-Rg Q acid ,cn -v-cooa,

base

ri -v-coon,

carbonyl reduct on zCl-h-V-COOR;

and V is C,,H,,,-OCR,,R,,, C,,,H,,,,-OCR,, R,-CR-,R,,CH=CHC,,H,,,OCR,R,,-- (cis or trans), -cH=cH-c,H,,-o cR,R,-cR,R,- (cisor trans), C II CC,,H ,,OCR,R,,, or -C- I C--C,H -OCR R -CR R wherein RR R R C,,H,,,, C,,,H,,,,, C,H,,, and C H are as defined above, with theproviso that V is --C,,H ,,-OCR,,. Rgor C,,,H ,,,-O-CR R,;CR R when A is-CH,--CH, The 3-oxa and 4-oxa PGE type compounds Of formulas XXVI andXXVli are transformed to the corresponding 3-oxa and 4-oxn PGFm. PGF B,PGA and P08 compounds by analogous reactions.

The various 3-oxa and 4-oxa dihydro-PGE,, dihydro- PGF dihydro-PGFdihydro-PGA and dihydro-PGB, type compounds encompassed by formulasXXIV, XXV, XXXlV, XXXV, XLlV, XLV, UV, and

23 24 LV are prepared by carbon-carbon double bond reduc- CHART B tionof the corresponding PGE, PGF PGF 8 PGA,

and P68 type compound containing a trans double bond in thehydroxy-containing side chain. A cis or trans double bond or anacetylenic bond can also be CH w present in the carboxy-terminated sidechain of the un- 2- -COOR saturated reactant, and will be reduced at thesame I time to CH,CH,-. For example, dihydro-3-oxa- I PGE is produced byreduction of 3-oxa-PGE,, 3-oxa- H i PGE or 5,6-dehydro-3-oxa-PGE,.

dl lml de or These reductions are carried out by reacting the unhydrogensaturated PGE, PGF PGF PGA, 0r PGB type t lyst compound with diimide,following the general procedure described by van Tamelen et al.. J. Am.Chem. Soc., 83. 3726 l96l See also Fieser et al., Topics in o ,C H;-W-CO0R, Organic Chemistry." Rheinhold Publishing Corp., New York, pp.432-434 (1963) and references cited Q therein. The unsaturated acid orester reactant is mixed with a salt of azodiformic acid, preferably analkali 2 metal salt such as the disodium or dipotassium salt, in Q thepresence of an inert diluent. preferably a lower alkanol such asmethanol or ethanol, and preferably in the absence of substantialamounts of water. At least one molecular equivalent of the azodiformicacid salt is used for each multiple bond equivalent of the unsaturatedreactant. The resulting suspension is then stirred, 11 2 -CO0R 1preferably with exclusion of oxygen, and the mixture is made acid,advantageously with a carboxylic acid such as acetic acid. When areactant wherein R, is hydrogen is used, that carboxylic acid reactantalso serves to ncidify an equivalent amount of the azodiformic acidsalt. A reaction temperature in the range about 10 to (H M de or about40 C. is usually suitable. Within that temperahydrogen ture range, thereaction is usually complete within less cats I ys t than 24 hours. Thedesired dihydro product is then iso- V lated by conventional methods,for example. evaporation of the diluent, followed by separation frominorganic materials by solvent extraction.

In the case of the 3-oxa and 4-oxa unsaturated PGE,

PGF a and PGF type reactants. the reductions to the corresponding 3-oxaand 4-oxa dihydro-PGE CH -W-CO0R dihydro-PFG and dihydro-POP, compoundsare also carried out by catalytic hydrogenation. For that CHaCHz-LR:

purpose, palladium catalysts, expecially on a carbon ll carrier, arepreferred. It is also preferred that the hy- Ho Q drogcnation be carriedout in the presence of an inert liquid diluent, for example, methanol,ethanol, dioxane, ethyl acetate, and the like. Hydrogenation pressuresranging from about atmospheric to about o CH p.s.i., and hydrogenationtemperatures ranging from {I 2 1 about 0 to about 100 C. are preferred.The resulting dihydro product is isolated from the hydrogenation re- Haction mixture by conventional methods, for example,

removal of the catalyst-by filtration or centrifugation, Q followed byevaporation of the solvent. l d mi de Diimide reductions and catalytichydrogenations to produce the various novel 3-oxa and 4-oxa dihydrocompounds of this invention from the corresponding .l-oxu and 4-oxa POEPOF POP], PGA and PUB, type compounds are shown in Chart B, wherein Q.R,. R,, and are as defined above. and W is -C,,H- 65 2,.O-CR R or-C,,,H,,,.0CR.R CR R,, C H C H; -C 'Rg wherein C ll C l-l R R,, R and R,are as dell fined above.

CH -W-COOR 25 CHQRT B eontl nued o CCCH -W-COOR,

H c-c( These diimide reductions and catalytic hydrogenations to producethe same novel 3-oxa and 4-oxa dihydro compounds of this invention fromthe corresponding 3-oxa and 4-oxa PGE,, PGF PCS-F PGA,, and PCB, typecompounds and also from the corresponding compounds with atrans-ethylenic or an acetylenic linkage in place of the cis-ethyleniclinkage in the carboxyl-terminated side chain, are shown in Chart C,wherein Q, R R and are as defined above, U is cis-Cl-l=CH-,trans-CH=CH-, or C I C-, and Y is -C,,H,,'-OCR,R, or --C,,H,,,OCR,. RCR-,R,, wherein p, q, R R R and R, are as defined above.

The 3-oxa and 4-oxa compounds of the PGE,, PGF, POP PGA and PGB typewherein the carbon-carbon double bond in the carboxy-terminated sidechain is in cis configuration are prepared by reduction of thecorresponding acetylenic 3-oxa and 4-oxa compounds, i.e., those with acarbon-carbon triple bond in place of said carbon-carbon double bond.For that purpose, there are used any of the known reducing agents whichreduce an acetylenic linkage to a cis-ethylenic linkage. Especiallypreferred for that purpose are diimide or hydrogen and a catalyst, forexample, palladium (5%) on barium sulfate, especially in the presence ofpyridine. See Fieser et al., Reagents for Organic Synthesis," pp.566-567,- John Wiley & Sons, lnc., New York, NY. (i967). Thesereductions are shown in Chart D, wherein Q, R R,, and are as definedabove, and Y is -C,H,,O-CR,,R, or -C,H,,-O-CR.R, CR R, These 3-oxa and4-oxa cis compounds of the PCB PGFra PGF, 5 PGA,, and P08, type are alsoprepared as described hereinafter.

CHART C ,cn -u-v-cook,

H IC not H c-a,

ll Q

dl lmlde or hydrogen catalyst 26 CHART C continued ,fiHzcHzcHz-v-cooa,:LCH CH -C-R Ho a a u 2 CH2-U-Y-C0OR1 H Ho H fi-Ra dl lmlde or hydrogencatalyst t/ 2CHzCH -Y-C00R CH CH -fi-R I 0 l/1 CH -U-Y-C0OR H C=C H C-Rzll Q dl lml de 0 \QICHQCHICH2'Y'COOR1 CH cH -fi-R 0 @ICH -U-Y-COOR H c-cH C-Rz ll Q dl lml de 0 dH CH CH -Y-COOR, cHacHg fi-Rz 27 CHART D &ICHIIH l 0' H ll Q E cns-c c-v-coon,

I I H C-Ra ll Q 28 CHART D contl nued The 3-oxa and 4-oxa POE typecompounds of formu- Ias XVIII to XXIII except wherein R, is hydrogen,and the 3-oxa and 4-oxa PGA type compounds of formulas XXXVIII to XLIIIexcept wherein R, is hydrogen are prepared by the series of reactionsshown in Chart E, wherein Q, R,, and V are as defined above, R, and Rarealkyl of one to 4 carbon atoms, inclusive, R is the same as the abovedefinition of R, except that R, does not include hydrogen, R is alkyl ofone to 5 carbon atoms, inclusive, and indicates exo or endoconfiguration with respect to the moiety attached to the cyclopropanering.

The 3-oxa and 4-oxa PGE, type compounds of formulas XVIII and XIX, the3-oxa and 4-oxa 5,6-dehydro-PGE, type compounds of formulas XXII andXXIII, the 3-oxa and 4-oxa PGA, type compounds of formulas XXXVIII andXXXIX, and the 3-oxa and 4-oxa 5,6-dehydro-PGA, type compounds offormulas XLII and XLllI are also prepared by the series of reactionsshown in Chart F, wherein 0, R R R and R are as defined above. 2 is-C,,H,,,-O-CR,R -'-C,,,H,,,,--OCR,,R,CR,R,,, C I CC,,H- -OCR5RQ, OI C ICC H OCR,-, R,CR R,. and indicates exo or endo configuration withrespect to the moiety attached to the cyclopropane ring.

It should be observed regarding the series of reactions shown in ChartsE and F, that the re action starting with glycol LX in Chart E aresimilar to the reactions starting with glycol LXVII in Chart F. The onlydifferences here are the definitions of the divalent moieties V (ChartE) and Z (Chart F). V includes saturated, cis and trans ethylenic, andacetylenic divalent moieties. Z is limited to the saturated andacetylenic divalent moieties encompassed by V.

QHART E LVI ll H-(iH-Ra O f C n 12 31 QEART F continued In other words,final 3-oxa and 4-oxa PGE type compounds of formula LXII (Chart E)encompass com pounds of formulas XVIII to XXIII. Final 3-oxa and 4-oxaPGA type compounds of formula LXIII (Chart E) encompass compounds offormulas XXXVIII to XLIII. On the other hand, final 3-oxa and 4-oxa PGEtype compounds of formula LXIX (Chart F) encompass only compounds offormulas XVIII, XIX. XXII. and XXIII, and final 3-oxa and 4-oxa PGA typecompounds of fon'nula LXX (Chart F) encompass only compounds of formulasXXXVIII, XXXIX, XLII, and XLIII.

As will subsequently appear, an acetylenic intermediate of formula LIX,formula LX, or formula LXVII is transfonned by reduction to thecorresponding cis or trans ethylenie intermediates-of formulas LIX orLX, and an acetylenic intermediate of fon'nulas LIX, LX, or LXVII, or acis or trans ethylenic intermediate of formulas LIX or LX istransfon'ned by reduction to the corresponding saturated intermediate offon'nulas LIX, LX, or LXVII.

The initial bicyclo-ketone reactant of formula LXV in Chart F is alsoused as an initial reactant to produce the initial bicyclo-ketone cyclicketal reactant of formula LVIII in Chart E. The reactionsof Chart 6 willproduce cyclic ketal LVIII. Therein THP is tetrahydropyranyl, and d: isphenyl.

The bicyclo-ketone reactant of formula LXV exists in four isomericforms, exo and endo with respect to the attachment of the Cl-I=CHR,moiety, and cis and trans with respect to the double bond in thatmoiety. Each of those isomers separately or various mixlures thereof areused as reactants according to this invention to produce substantiallyOTHP LXXII 32 CHART G contl nued a vie several steps LXV CH CH-Ra LXXlllLVlll the same final 3-oxa or 4-oxa PGE or PGA type product mixture.

The process for preparing either the axe or endo configuration of theformula-LXV bicyclo-ketone is known to the art. See Belgian Pat. No.702,477; reprinted in Farmdoc Complete Specifications, Book 714, No.30,905, page 313, Mar. 12, 1968. See West Germany OffenlegungsschriftNo. 1,937,912; reprinted in Farmdoc Complete Specifications, Book No.14, No. 6869 R, Week R Mar. l8, I970.

In said Belgian Pat. No. 702,477, a reaction sequence capable of formingexo ketone LXV is as follows: The hydroxy of 3-cyclopentenol isprotected, for example, with a tetrahydropyranyl group. Then adiazoacetic acid ester is added to the double bond to give an exoendomixture of a bicyclo[3.l.0]hexane substituted at 3 with the protectedhydroxy and at 6 with a esterified carboxyl. The exo-cndo mixture istreated with a base to isomerize the endo isomer in the mixture to moreof the exo isomer. Next, the carboxylate ester groups at 6 istransformed to an aldehyde group, CHO. Then, said aldehyde group istransformed by the Wittig reaction, in this case to a moiety'of theformula CH= CH-R, which is in exo configuration relative to the bicycloring structure. Next, the protective group is removed to regenerate the3-hydroxy which is then oxidized, for example, by the Jones reagent,i.e., chromic acid (see J. Chem. Soc. 39 (1946)), to give said exoketone LXV.

Separation of the cis-exo and trans-exo isomers of LXV is described insaid Belgian Pat. No. 702,477. However, as mentioned above, thatseparation is usually not necessary since the cis-trans mixture isuseful as a reactant in the next process step.

COOCHs LXX l V Compound LXXIV. is prepared by reactingendo-bicyclo[3.1.0]-hexane 3-o1-6-carboxylic acid methyl ester which isthen reacted with dihydropyran in the presence of a catalytic amount ofPOCl, to give the desired compound. This is then used as described insaid Offenlegungsschrift No. 1,93 7,912 to produce the endo form ofbicyclo ketone LXV.

As for exo LXV, the above process produces a mixture of endo-cis andendo-trans compounds. These are separated as described for theseparation of exo-cis and exo-trans LXV, but this separation is usuallynot necessary since, as mentioned above, the cis-trans mixture is usefulas a reactant in the next process step.

in the process of said Belgian patent and saidWest' GermanyOffenlegungsschrift, certain organic halides, e.g., chlorides andbromides, are necessary to prepare the Wittig reagents used to generatethe generic moiety, Cl-1-CHR, of bicyclo-ketone LXV. These organicchlorides and bromides R,--Cl-l,-Cl and R,-Cl-l,-Br, are known in theart or can be prepared by methods known in the art.

To illustrate the availability of these organic chlorides consider firstthe above-described 3-oxa and 4-oxa PGE-type compounds 'of' formulasXVlll to XXVll wherein G is alkyl of one to carbon atoms, inclusive,substituted with zero, one, 2, or 3 fluoro.

For those products wherein R, is alkyl of one to ID carbon atoms,substituted with zero to 3 fluoro atoms, there are available themonohalo hydrocarbons, e.g., bromo-(or chloro-)methane, -ethane,-propane, -pentane, -octane, and -decane; and the monohalofluorohydrocarbons, e.g., CH FCl, C1-l,FCl-l,Br, CHF,CH,CI,

CH (CH );,CF (CH CH CL as described in Aliphatic Fluorine Compounds", A.M. Lovelace et al., Am. Chem. Soc. Monograph Series 1958, Reinhold Publ.Corp. Those halides not available are prepared by methods known in theart by reacting the corresponding primery alcohol R,CH OH with P0,, PBror any of the other halogenating agents useful for this purpose.Available alcohols include CH CH(CF )CH OH. (CH ),CHCH CH,OH, (CH),-,CCH OH. CF,CH(CH;,)CH,CH,OH, for example. For those halides of theformula R:-CH Hal wherein Hal is chloro or bromo R, is R,,(CH,),,, dbeing one, 2, 3, or 4, and R being isobutyl, tert-butyl,3,3'difluorobutyl, 4,4-difluorobutyl, or 4,4,4-trifluorobutyl, theintermediate alcohols are prepared as follows.

in the case of R being isobutyl or tert-butyl, known alcohols areconverted to bromides, thence to nitriles with sodium cyanide, thence tothe corresponding carboxylic acids by hydrolysis, and thence to thecorresponding primary alcohols by reduction, e.g. with lithium aluminumhydride, thus extending the carbon chain one carbon atom at a time untilall primary alcohols are prepared.

in the case of R being 3,3-difluorobutyl, the necessary alcohols areprepared from keto carboxylic acids of the formula, CH CO(CH ),COOH,wherein r is 2, 3, 4, 5, or 6. All of those acids are known. The methylesters are prepared and reacted with sulfur tetrafluoride to produce thecorresponding CH CF- =-(CH ),--COOCH compounds, which are then reducedwith lithium aluminum hydride to CH CF- ,(CH,),--CH,OH. These alcoholsare then transformed to the bromide or chloride by reaction with PB OIPCig.

in the case of R being 4,4-difluorobutyl, the initial reactants are theknown dicarboxylic acids, HOO- C(CH;) -COOH, wherein f is 3, 4, 5, 6, or7. These dicarboxylic acids are esterified to CH OOC-(CH ),COOCH andthen half-saponified, for example with barium hydroxide, to giveHOOC-(CH ),-COOCH,. The free carboxyl group is transformed first to theacid chloride with thionyl chloride and then to an aldehyde by theRosenmund reduction. Reaction of the aldehyde with sulfur tetrafluoridethen gives CHF,-(CH,),COOCH which by successive treatment with lithiumaluminum hydride and PBr or PCl gives the necessary bromides orchlorides,

in the case of R being 4,4,4-trifluorobutyl, aldehydes of the fonnulaCl-hOOC-(CHW-CHO are prepared as described above. Reduction of thealdehyde with sodium borohydride gives the alcohol CH;OOC-(CH;),CH;OH.Reaction with a hydrogen halide, for example hydrogen bromide, gives thecorresponding halocarboxylic acid which by reaction with sulfurtetrafluoride gives the necessary CF;(CH,),-CH,-Br or CF;,-(CH CH -'Cl.

For the above reactions of SF,, see US. Pat. No. 3,211,723 and J. Org.Chem. 27, 3164 (l962).

As mentioned above, formula XVlll-to-LVll compounds with an alpha-fluorosubstitutent in a straight chain 3 to 7-carbon R i.e., R being CHF-(CH),-CH wherein g is one, 2, 3, 4, or 5, represent preferred embodimentsamong the novel 3-oxa and 4-oxa compounds of this invention. Amongthose, for exampie. is 3-oxa-l6-fluoro-PGE,. The formula-LXVbicycloketones necessary to produce those monofluoro compounds areadvantageously prepared by reacting either of the above-mentionedbicyclo-aldehydes, exo or endo, with a Wittig reagent prepared from CH.(CH,),-COCH,-Br and triphenylphosphine. The aldehyde group is therebytransformed to The resulting unsaturated ketone is reduced to thecorresponding EH CH-CH-- H-(Clhh-CH;

compound. Then --OH in that group is replaced with fluoro by knownmethods, for example, directly by reaction with 2-chloro-l,l,l-trifiuorotriethylamine or indirectly, for example, by transformingthe hydroxy to tosyloxy or mesyloxy, and reacting the resulting compoundwith anhydrous potassium fluoride in diethylene glycol.

The transfonnation of bicyclo-ketone-olefin LXV to glycol LXXlll iscarried out by reacting olefin LXV with a hydroxylation reagent.Hydroxylation reagents and procedures for this purpose are known in theart. See, for example, Gunstone, Advances in Organic Chemistry, Vol. I,pp, 103-147, lnterscience Publishers, New York, N.Y. (1960). Especiallyuseful hydroxylation reagents for this purpose are osmium tetroxide andperforrnic acid (formic acid plus hydrogen peroxide). Various isomericglycols are obtained depending on such factors as whether olefin LXV iscis or trans and endo or exo, and whether a cis or a trans hydroxylationreagent is used. These various glycol mixtures can be separated intoindividual isomers by silica gel chromatography. However, thisseparation is usually not necessary, since all isomers of a particularglycol are equally useful as intermediates according to this inventionand the processes outlined in Chart E to produce final products offormulas um and DO", and then, according to Chart A, B, C, and D toproduct the other final products of this invention.

The transformation of glycolLXXlll to'the cyclic ketal of fonnula LVlll(Chart E) is carried out by',re-

acting said glycol with a dialkyl ketone of the formula wherein R and Rare alkyl of one to 4 carbon atoms, inclusive, in the presence of anacid catalyst, for example potassium bisulfate or 70% aqueous perchloricacid. A large excess of the ketone and the absence of water is desirablefor this reaction. Examples of suitable dialkyl ketones are acetone,methyl ethyl ketone, diethyl ketone, methyl propyl ketone, and the like.Acetone is preferred as a reactant'in' this process.

Referring again to Chart E, cyclic ketal LVlll is transformed tocyclicketal LIX by alkylating with an alkylation agent of the formulaHalCH- ,-V-COOR, wherein R and V are as defined above, and Hal ischlorine, bromine, or iodine. Similarly, referring to Chart F, olefinLXV is transformed to olefin LXVl by alkylating with an alkylation agentof the formula Hal-CH Z-COOR wherein R 2 and Hal are as defined above.

Any of the alkylation procedures known in the art to be useful foralkylating cyclic ketones with alkyl halides and haloalkanoic esters areused for the transformutions of LVlll to LIX and LXV to LXVl. See, forexample, the above-mentioned'Belgian Pat. No. 702,477 for proceduresuseful here and used there to carry out similar alkylations, e.g.,employing the bicycle enamines.

For these alkylations, it is preferred that Hal be bromo or iodo. Any ofthe usual alkylation bases, e.g., alkali metal alkoxides, alkali metalamides, and alkali metal hydrides, are useful for this alkylation.Alkali metal alkoxides are preferred, especially tert-alkoxides. Sodiumand potassium are preferred alkali metals. Especially preferred ispotassium tert-butoxide. Preferred diluents for this alkylation aretertrahydrofuran and l,'2-dimethoxyethane. otherwise, procedures forproducing and isolating the desired formula LlX and LXVl compounds arewithin the skill of the art.

These alkylation procedures produce mixtures of alpha and betaalkylation products, i.e., a mixture of the formula-LIX products whereinthe CH- ,VCOOR, moiety is attached in alpha configuration, withcorresponding compounds having that moiety attached in betaconfiguration, or a mixture of the formula-LXV! products withcorresponding compounds having the CH,-ZCOOR, moiety in the betaconfiguration. When about one equivalent of base per equivalent offormula LXV or LVIll ketone is used, the alpha configuration usuallypredominates. Use of an excess of base and longer reaction times usuallyresult in production of larger amounts of beta products. Thesealpha-beta isomer mixtures are separated at this stage or at anysubsequent stage in the multi-step processes shown in Charts E and F.Silica gel chromatography is preferred for this separation.

The necessary alkylating agents for the abovedescribed alkylations,i.e., compounds of the formulas Hal-CH,-V-'-COOR, and Hal-CH,-Z--COOR,are prepared by methods known in the art.

There are eight groups of compounds encompassed by these two genera ofalkylating agents. Alkylating agents of the formula Hal--CH,-ZCOOR,include compounds of the following formulas:

These alkylating agents of formulas LXXV to LXXXll are accessible tothose of ordinary skill in the art. For example, the 3-oxa alkylatingagents of fonnulas LXXV, LXXVILLXXIX, and LXXX are advantageouslyprepared by reacting an alpha-hydroxy ester or acid of the formulaHO-CRJh-COOR wherein R,, R and R, are as defined above, with a compoundof the formula, .I-CH,-CnH,,,-G, J-Cl-h-C- I C-C,H,,-G, andJCi-l,-CH=Cl-lC,l-l,,-G, respectively, wherein C,,H,,, and C,,H,, are asdefined above, J is chloro, bromo, iodo, or a group transformable to oneof those, for example, tetrahydropyranyloxy or mesyloxy, and G ischloro, bromo, iodo, mesyloxy, tosyloxy, or the like, in the presence ofa strong base, for example, sodium hydride when R, is acarbon-containing group, and lithium diisopropyl amide when R, ishydrogen.'Alternatively, an alphabromo ester or acid of the formulaBr-CR R,COOR,, wherein R R and R. are as defined above, is reacted inthe presence of a similar strong base with a compound of the formula.l-CH, C,,H,,,-OH,JCH,C I C C,H,,Ol-i, or .l-Cl-l- ,-CH=CHC,H,,-OH. Whenboth R, and R. in the ester are alkyl, it is preferred to use thehydroxy acid or ester route. When there are two alkyl groups'inC,,l-l,,, or C,,H,, on the carbon to which --OH or -G is attached, it ispreferred to use the bromo acid or ester route. When aformula LXXV,LXXVll, LXXIX, or LXXX alkylating agent is desired wherein both R, andR, are alkyl and C,,l-l,,, or C,H,, has two alkyl groups attached to thecarbon to which --0-- is attached, it is preferred that G be mesyloxy ortosyloxy, or that the Br of the bromo acid or ester be replaced withmesyloxy or tosyloxy, whereupon bases and reaction conditions known inthe art may be used, for example, potassium tert-butoxide in dimethylsulfoxide. Alternatively, this group of tetraalkyl compounds isadvantageously prepared by using the hydroxy acid or ester route with acompound wherein G is chloro, or by using the bromo acid or ester routewherein the bromo is replaced with chloro, using freshly precipitatedwet magnesium hydroxide in an inert solvent suspension as the base.Alternatively this group of tetraalkyl compounds is ad- 38 vantageouslyprepared by the hydroxy acid or ester route wherein G is iodo, andsilver oxide is used as the base. Any of these alternative routes is, ofcourse, useful to make the other compounds within the scope of formulasLXXV, LXXVll, LXXlX, and LXXX.

An alternative procedure generally applicable to the production of thealkylating agents of formulas LXXV, LXXVll, LXXIX, and LXXX comprisesreacting a compound of the formula J-CH,-C,,H ,,OH, J-CH,-c c-c,H.,,-oH,or J-CH CH= CH-C,H ,,OH with an ethylene oxide of the formula wherein R,and R are as defined above, in the presence of an acid catalyst, e.g.,hydrochloric acid, sulfuric acid, or boron trifluoride. The alcoholwhich is usually the major product, i.e., .l-CH -C,,H-,,,OCR R,CH,OH,.l-Cl-l=-C II CC,,H,,,-O-CR R,-CH,0H, or cis or trans J-CH,-CH=CHC,,H-,,,-OCR R CH,OH, is isolated, oxidized to the corresponding carboxylicacid with Jones reagent, and the acid esterified (R The 4-oxa alkylatingagents of formulas LXXVl, LXXVlll, LXXXl, and LXXXll are advantageouslyprepared as described above for the 3-oxa compounds, combining compoundsof the formula J CH --C,,,H- ,,,,G, J-CH,C,,,H ,,,OH, J-CH -C I C-C,,H,,,--G, .l--CH,C I CC,,H .,-OH, .l-CH -CH= Cl-lC,,H -G, and J-CH CH=CHCH OH, with B-hydroxy acids or esters and ,B-halo acids or esters of theformulas HO--CR,,R,,--CR,R,,COOR and Br-CR R,--CR R,,COOR,, ortrimethylene oxides of the formula All of the procedures, preferences,and alternatives described above for the preparation of the 3-oxaalkylating agentsare applicable to the preparation of these 4'oxaalkylating agents.

The alkylating agents of formulas LXXV to LXXXll are esters. When analpha or beta hydroxy acid or bromo acid is used as a reactant asdescribed above, the resulting product is a carboxylic acid. This acidis esterified to the corresponding formulas LXXV-to-LXXXIl alkylatingagent by known procedures. As will be described hereinafter, the estermoiety R is chosen according to the desired type of final 3-oxa or 4-oxaprostaglandin-like product.

The alpha-hydroxy, alpha-halo, beta-hydroxy, and beta-halo acids andesters and the ethylene and trimethylene oxides used as described aboveto produce the formula LXXV to LXXXll alkylating agents are all known inthe art or are readily accessible through known methods to those ofordinary skill in the art.

1. AN OPTICALLY ACTIVE COMPOUND OF THE FORMULA:
 2. A racemic compoundaccording to claim
 1. 3. An optically active compound according toclaim
 1. 4. A compound according to claim 3 wherein CnH2n is straightchain alkylene of one to 5 carbon atoms, inclusive.
 5. A compoundaccording to claim 4 wherein CnH2n is trimethylene.
 6. A compoundaccording to claim 5 wherein R5, R6, R7, and R8 are hydrogen or methyl,being the same or different.
 7. A compound according to claim 6 whereinR5, R6, R7, and R8 are hydrogen.
 8. A compound according to claim 7wherein R2 is pentyl.
 9. A compound according to claim 8 wherein
 10. Acompound according to claim 8 wherein
 11. A compound according to claim10 wherein R1 is hydrogen or alkyl of one to 4 carbon atoms, inclusive,including the pharmacologically acceptable salts thereof when R1 ishydrogen.
 12. A compound according to claim 11 wherein R1 is hydrogen oralkyl of one to 4 carbon atoms, inclusive.
 13. A compound according toclaim 12 wherein R1 is hydrogen, methyl or ethyl.
 14. 4-Oxa-PGA1, acompound according to claim
 13. 15. 4-Oxa-PGA1, methyl ester, a compoundaccording to claim
 13. 16. 15-Methyl-4-oxa-PGA1, a compound according toclaim
 13. 17. 15-Methyl-4-oxa-PGA1, methyl ester, a compound accordingto claim
 13. 18. An optically active compound of the formula:
 19. Aracemic compound according to claim
 18. 20. An optically active compoundaccording to claim
 18. 21. A compound according to claim 20 whereinCnH2n is straight chain alkylene of one to 5 carbon atoms, inclusive.22. A compound according to claim 21 wherein CnH2n is trimethylene. 23.A compound according to claim 22 wherein R5, R6R7and R8 are hydrogen ormethyl, being the same or different.
 24. A compound according to claim23 wherein R5, R6, R7, and R8 are hydrogen.
 25. A compound according toclaim 24 wherein R2 is pentyl.
 26. A compound according to claim 25wherein
 27. A compound according to claim 25 wherein
 28. A compoundaccording to claim 27 wherein R1 is hydrogen or alkyl of one to 4 carbonatoms, inclusive, including the pharmacologically acceptable saltsthereof when R1 is hydrogen.
 29. A compound according to claim 28wherein R1 is hydrogen or alkyl of one to 4 carbon atoms, inclusive. 30.A compound according to claim 29 wherein R1 is hydrogen, methyl orethyl.
 31. A compound according to claim 30 wherein the C-5 to C-6double bond in the carboxyl-terminated side chain is in the cisconfiguration.
 32. 4-Oxa-PGA2, a compound according to claim
 31. 33.4-Oxa-PGA2, methyl ester, a compound according to claim
 31. 34.15-Methyl-4-oxa-PGA2, a compound according to claim
 31. 35.15-Methyl-4-oxa-PGA2, methyl ester, a compound according to claim 31.36. An optically active compound of the formula:
 37. An optically activecompound of the formula:
 38. An optically active compound of theformula: